Excessive activation of NMDA receptors (NMDAR) causes neuronal death, a process central too many neurological disorders, including traumatic injury, stroke, and seizure. Pre-conditional actions such as low-dose NMDA treatment, sub-lethal ischemia, or mild seizure can effectively prevent neuronal death caused by subsequent harsh insults, suggesting that mild stress conditions can be beneficial and indicating a possible niche for therapeutic intervention. We have recently established that NMDAR activation regulates the mammalian target of rapamycin (mTOR) pathway. This pathway, previously understood to influence cell growth in response to growth factors, nutrients, and other stress conditions, including oxidative stresses and hypoxia, may also regulate cell death. Our preliminary studies found that neuronal death elicited by NMDA treatment is attenuated upon leucine starvation, a stress condition that is known to inhibit the mTOR pathway. Several components of the mTOR pathway appear to be associated with epilepsy. To further elucidate the molecular mechanism of the mTOR pathway in neuronal death and its involvement in epileptogenesis, we will determine whether the pro- survival factor Akt, which acts both up- and downstream of mTOR, mediates the neuroprotection conferred by inhibition of mTOR (Aim I). Nutrient depletion and mTOR inhibition are known to activate the process of autophagy. We will determine whether autophagy is involved in neuroprotection (Aim II). Finally, we will determine whether inhibition of the mTOR pathway prevents neuronal loss in animal models of epilepsy and attenuates the development of spontaneous seizure (Aim III). Accomplishing the experiments proposed in these three aims will provide insight into the molecular mechanisms of mTOR in neuronal death and in epileptogenesis. Rapamycin (Sirolimus) has been used as immunosuppressant for organ transplantation and was recently put on clinical trial in patients with tuberous sclerosis complex (TSC). Furthermore, the leucine-starvation approach is clinically manageable in current medical settings. As epilepsy is a devastating neurological disorder with few preventive approaches available, any positive results from the proposed study could be readily translated into new clinical strategies for epilepsy prevention, presumably without many of the barriers normally encountered by traditional development of therapeutic drugs. PUBLIC HEALTH RELEVANCE Results from our studies will improve our understanding of the role of the mTOR signaling pathway in epilepsy as well as other neurological disorders such as stroke and traumatic brain injury. It may also lead to new pharmacological and diet interventions for those neurological disorders.